High-purity cochleates engineered with DOTAP: Unlocking new potential for drug delivery

Cochleates are multilamellar lipid–calcium precipitates with potential for oral delivery of poorly soluble or irritant drugs, but their heterogeneity has limited translation. Here, we report the engineering of highly pure, structurally uniform cochleates using a cationic lipid (DOTAP) in combination with anionic phospholipids (DOPS, DMPS). CAP (capsaicin) was selected as a model drug due to its poor solubility, instability, and gastrointestinal side effects. DOTAP-containing cochleates (H) displayed well-defined rod-like morphology, reduced aggregation, and enhanced colloidal stability compared to conventional formulations (A–G). Physicochemical analysis (FE-SEM, SAXS, DSC, FTIR) confirmed strong CAP–lipid interactions, reduced crystallinity, and improved bilayer ordering. Encapsulation efficiency reached 93.3 % with loading of 196 mg/g, markedly higher than typical nanocarriers. In-vitro release showed suppressed burst effect and sustained diffusion-controlled release over 94 h, with cochleates H exhibiting the slowest release kinetics. Stability studies demonstrated excellent drug retention at physiological pH and moderate temperatures. Together, these findings establish DOTAP-engineered cochleates as a robust platform for oral delivery, offering high purity, reproducibility, and translational promise for hydrophobic or irritant drugs.